Inflammatory and immune reactions depend upon the recruitment and migration of circulating leukocytes to sites of injury or antigen exposure. Accumulation and activation of leukocytes result in the generation of numerous cytokines, growth factors, enzymes, and mediators, which participate in the further recruitment and activation of leukocytes, thereby augmenting and perpetuating the defense of the injured or antigen-exposed mammal.
When a particular type of leukocyte, namely the macrophage, is activated by bacteria, bacterial products, T lymphocyte-derived cytokines, and antigens, it responds by converting arginine into nitric oxide (NO). NO is just one of a number of highly toxic free-radicals, which include oxygen (O.sub.2 -), peroxide (H.sub.2 O.sub.2), and hydroxyl radicals (OH.multidot.). When released from macrophages as part of the host defense mechanism, NO contributes to leukocyte killing of bacteria, fungi and tumor cells. The extracellular release of NO from other cells and tissues, such as endothelium, may cause vasodilation and tissue damage.
NO is produced by the action of a NO synthase. Some cells, such as macrophages, express an inducible NO synthase, which produces large quantities of NO upon stimulation. In contrast, cells, such as neurons and endothelial cells, possess a constitutive form of this enzyme. In other words, the NO synthase possessed by these cells produces NO continuously at a constant level.
Although meant to be protective, reactive nitrogen intermediates can actually suppress host defenses during some infections, such as listeriosis and brucellosis, and thus play a pathogenic role in some infectious diseases. The NO pathway also may contribute to the destructive aspects of an immune response, particularly in chronic inflammation, by the nonspecific destruction of cellular metabolic machinery within a circumscribed area of NO release. Such nonspecific destruction, if excessive, can lead to any one of a number of inflammatory diseases or syndromes, including autoimmune diseases, such as rheumatoid arthritis.
Interfering with the production of NO provides a means of modulating inflammatory reactions and of inhibiting the destructive sequelae of a chronic inflammatory immune response. However, given that NO is highly reactive by nature, inhibitors which inhibit the NO radical directly would not be expected to be as effective as an inhibitor which blocks the synthesis of the NO radical.
It is an object of the present invention to provide a method for the treatment of chronic and acute inflammatory conditions, including autoimmune diseases. More specifically, it is an object of the present invention to provide a method for the treatment of such conditions wherein an agent that decreases the amount of nitric oxide present is administered. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.